Every hour of every day, one American dies of oral cancer. It is a challenging disease to treat successfully and the mortality rate associated with oral cancer has not improved significantly in the last 40 years. The focus and the underlying goal of this project is to identify specific genes which provide growth advantage in HPV positive and/or HPV negative oral carcinomas through functional genomic screening. The identification of these gene targets can then be exploited in treating oral cancer patients based on their etiologic background and risk factors involved. We propose to undertake high-throughput RNA interference screening using siRNA library ('7000 genes) to systematically identify genes or "Achilles heel" targets that mediate proliferation of the HPV dependent as well as HPV-independent oral cancer cells (Specific Aim 1). Subsequently, these genes will be validated (Specific Aim 2) by confirming siRNA mediated gene knockdown using additional siRNAs to the target genes. Using these gene targets, knowledge mining would be done to identify specific pathways that might contribute significantly to the proliferative potential of either HPV positive, HPV negative or both the subtypes of oral cancer. Further validation will be done by characterizing protein expression of identified specific target genes in oral cancer tissue samples using tissue microarrays (Specific Aim 3). We aim to be able to differentiate the HPV positive and negative oral cancers and show the differences in their response and/or dependency on specific signaling pathways based on the etiology. We hypothesize that this functional genomics based approach will identify the context of genetic perturbations associated with tumor progression that render the cancer cells to uncontrolled proliferation and help us identify specific drug targets for treating cancer patients based on the risk factors associated with their specific disease. This initiative will be our step towards personalized medicine and these validated genes could be of direct relevance to clinical exploitation in oral cancer patients.